The present invention relates to novel polymorphic crystalline forms of anhydrous (3S-trans)-2-[3,4-dihydro-4-hydroxy-3-(phenylmethyl)-2H-1-benzopyran-7-yl]-4-(trifluoromethyl)-benzoic acid, and to methods for the preparation thereof. (3S-trans)-2-[3,4-dihydro-4-hydroxy-3-(phenylmethyl)-2H-1-benzopyran-7-yl]-4-(trifluoromethyl)-benzoic acid, hereinafter compound(I), is a benzopyran-derived antagonist of leukotriene B4 (hereinafter, xe2x80x9cLTB4xe2x80x9d), and is therefore useful in the treatment of numerous diseases including inflammatory diseases. Compound (I) has the chemical formula C24H17O4F3, is also appropriately named as [(+)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid], and has the following stereospecific structure. 
The invention also relates to a novel crystalline salt and a novel crystalline hydrate of compound (I). The novel crystalline forms of the invention possess one or more characteristics selected from enhanced thermal stability, improved solubility in aqueous solvents, improved bioavailability, ready isolation from water-wet solvents, and capacity to be formulated as a pharmaceutical composition using wet granulation techniques, that surprisingly facilitate the use of compound (I) in medical applications.
Leukotrienes are a class of compounds derived from the 20-carbon fatty acid skeleton of arachidonic acid which function as locally acting hormone-like chemical mediators. Leukotrienes define one major division of the eicosanoids, a large family of chemical mediators, derived from 20 carbon-polyunstaturated fatty acids, and which also includes the lipoxins, thromboxanes, hydroperoxy fatty acids, and prostaglandins.
In general, synthesis of eicosanoids is stimulated by local tissue damage, hormonal stimuli, or via cellular activation pathways (such as binding of IgE immunoglobins to cell surface receptors). Unlike stored, pre-formed chemical mediators, eicosanoid lipid mediators typically appear in cells only after activation events. Eicosanoids, in turn, bind to specific cell surface receptors thereby mediating a wide variety of effects in numerous tissues. Antagonist compounds have been developed for various classes of eicosanoids that act to prevent the normal effects of eicosanoid-receptor binding.
In one recognized pathway, arachidonic acid is produced in activated cells from cell membrane phospholipids by the action of one or more lipase enzymes. Arachindonic acid is first transformed into an unstable epoxide, known as leukotriene A4 (LTA4) which can be enzymatically hydrated (via 5-lipoxygenase) to leuokotriene B4 (LTB4). Alternatively, via the action of the enzyme glutathione S-transferase, LTA4 may be covalently coupled to glutathione to form leuoktriene C4 (LTC4), from which leuoktriene D4 (LTD4), and leuoktriene E4 (LTE4), may be subsequently formed by elimination of xcex3-glutamyl and then glycinyl residues, respectively.
The cysteinyl leukotrienes (C4, D4 and E4) are likely the principal mediators of acute attacks of IgE-mediated bronchial asthma, and are more that 100-fold more potent than histamine, on a molar basis, at effecting bronchiole constriction. Accordingly, there is considerable interest in developing pharmaceuticals that interfere with leukotriene-mediated processes by acting as antagonists of leukotriene-receptor interactions.
The biological role of leukotriene B4 was first appreciated in the 1980s when addition of LTB4 to isolated neutrophils (a type of white blood cell) induced chemotactic, chemokinetic and aggregation responses, and increased adhesion of neutrophils to endothelial cell monolayers. Because of their capacity to engulf and destroy bacteria, for example, neutrophils play a key role in responding to sites of infection in the body. Neutrophils were also originally identified as a major source of LTB4. Subsequently it has been determined that other types of cells that participate in immune and inflammation-related pathways (i.e. monocytes, macrophages, keratinocytes, lymphocytes and mast cells) also produce LTB4 under circumstances likely associated with pathophysiologic stimulation. LTB4 has also been shown to participate in gene transcription and translation for various cytokines and their receptors in various T and B cells of the immune system. Taken together, these and other results indicate that LTB4 plays a broad role in inflammatory processes. That neutrophils both secrete and chemotactically respond to LTB4 strongly suggests a feedback mechanism to regulate the inflammatory response.
Generally speaking, the inflammatory response is a protective mechanism that facilitates response to local injury. For example, leakage of tissue fluids into the affected area facilitates contact with antibodies, and also permits the migration of white blood cells to directly combat any injurious agent. Unfortunately, an inflammatory response may be inappropriate, that is, it may continue for an excessive period of time or involve participation by inflammatory system components that, unfortunately, act to damage to the body, thereby contributing to, or even defining, a disease state. Accordingly, there are numerous circumstances where it is medically appropriate to interefere with inflammatory processes.
Since inflammatory pathways are involved in the pathology of numerous disease states, compounds that act as antagonists to leukotriene B4-mediated effects define a class of important pharmaceutical agents. The involvement of LTB4 in a variety of human inflammatory diseases, and other diseases, is also suggested by the effectiveness of potent LTB4 receptor antagonists in preclinical animal disease models (for a review, see H. J. Showell, et al., Journal of Pharmacology and Experimental Therapeutics, 285 (3), pp. 946-954, 1998, and original citations therein).
Pharmaceutical agents that inhibit the action of LTB4 are useful in the treatment of diseases induced by LTB4, or to which LTB4 contributes, including, without limitation, inflammatory disorders such as rheumatoid arthritis, osteoarthritis, inflammatory bowel disease; disorders of the skin including psoriasis, eczema, erythema, pruritis, and acne; stroke, and any disease marked by reperfusion injury; graft rejection; autoimmune diseases; allergy and asthma; and, for example, any other condition where marked neutrophil infiltration occurs. It will be recognized that more than one such state may occur simultaneously, or that an individual disease state may have more than one cause, nonetheless being treatable according to the practice of the present invention.
LTB4 antagonists are also disclosed in European patent publications 276 064 and 292 977 which refer respectively to (a) diphenyl ethers, benzophenones, and other compounds containing two phenyl groups, and (b) derivatives of 7-(3-alkoxy-4-alkanoyl-phenoxy)alkoxybenzopyran. Additional classes of LTB4 antagonists, and original citations thereto, are mentioned in H. J. Showell et al., xe2x80x9cInhibitors and Antagonists of Cyclooxygenase, 5-Lipoxygenase, and Platelet Activating Factorxe2x80x9d, in Inflammation: Basic Principals and Clinical Correlates, 3rd ed., J. I. Gallin et al., chapter 74, pp. 1177-1193, Lippincott, Philadelphia, Pa., 1999.
The compound of the present invention is disclosed generally in U.S. Pat. No. 5,552,435 which is incorporated by reference herein as if fully set forth.
It has now been discovered that anhydrous compound (I) can exist in crystalline, polymorphic forms, which differ from each other in their stability, physical properties, spectral data, and methods of preparation. It has also been discovered that particular salts and hydrates of compound (I) have properties that contribute to their usefulness as pharmaceuticals.
As aforementioned, each novel polymorphic crystalline form of compound (I) or salt or hydrate of compound (I), as herein described, possesses one or more characteristics (selected from enhanced thermal stability, improved solubility in aqueous solvents, improved bioavailability, ready isolation from water-wet solvents, and capacity to be formulated as a pharmaceutical composition using wet granulation techniques) that surprisingly facilitate the use of compound (I) in medical applications. U.S. Pat. No. 5,552,435 does not refer to the specific polymorphic crystalline forms of anhydrous compound (I), or the specific salt or hydrate, as herein described.
Accordingly, there are provided novel polymorphic forms of anhydrous crystalline (3S-trans)-2-[3,4-dihydro-4-hydroxy-3-(phenylmethyl)-2H-1-benzopyran-7-yl]-4-(trifluoromethyl)-benzoic acid, compound (I), 
and a novel salt, and hydrate of compound (I) as follows.
(i) A crystalline polymorph (xe2x80x9cAxe2x80x9d) of anhydrous (3S-trans)-2-[3,4-dihydro-4-hydroxy-3-(phenylmethyl)-2H-1-benzopyran-7-yl]-4-(trifluoromethyl)-benzoic acid is provided that exhibits an X-ray powder diffraction pattern having characteristic peaks, expressed in degrees 2xcex8, at approximately 5.490; 10.242; 10.791; 12.060; 12.460; 13.811; 16.033; 16.360; 17.054; 19.045; 19.647; 20.679; 21.053; and 21.663.
(ii) A crystalline polymorph (xe2x80x9cBxe2x80x9d) of anhydrous (3S-trans)-2-[3,4-dihydro-4-hydroxy-3-(phenylmethyl)-2H-1-benzopyran-7-yl]-4-(trifluoromethyl)-benzoic acid is provided that exhibits an X-ray powder diffraction pattern having characteristic peaks, expressed in degrees 2xcex8, at approximately 4.881; 13.585; 14.498; 14.720; 16.623 and 19.222.
(iii) The invention also provides crystalline monohydrate of (3S-trans)-2-[3,4-dihydro-4-hydroxy-3-(phenylmethyl)-2H-1-benzopyran-7-yl]-4-(trifluoromethyl)-benzoic acid.
In crystalline form, as generally observed, the monohydrate of (3S-trans)-2-[3,4-dihydro-4-hydroxy-3-(phenylmethyl)-2H-1-benzopyran-7-yl]-4-(trifluoromethyl)-benzoic acid exhibits an X-ray powder diffraction pattern having characteristic peaks, expressed in degrees 2xcex8, at approximately 4.464; 6.310; 7.827; 9.158; 13.218; 16.831; 18.315; 20.176; and 21.558.
(iv) The invention also provides an ethylene diamine (mono) salt of (3S-trans)-2-[3,4-dihydro-4-hydroxy-3-(phenylmethyl)-2H-1-benzopyran-7-yl]-4-(trifluoromethyl)-benzoic acid.
In crystalline form, as generally observed, the ethylene diamine (mono) salt of (3-S-trans)-2-[3,4-dihydro-4-hydroxy-3-(phenylmethyl)-2H-1-benzopyran-7-yl]-4-(trifluoromethyl)-benzoic acid exhibits an X-ray powder diffraction pattern having characteristic peaks, expressed in degrees 2xcex8, at approximately 6.829; 9.751; 12.270; 14.638; 15.776; 16.345; 16.554; 17.354; 19.468; 19.760; and 22.342.
All of the novel salts, hydrates, and anhydrous crystalline forms of compound (I) according to the practice of the invention possess the stereospecificity as shown in formula I.
As aforementioned, the particular novel polymorphs, salt and hydrate of the present invention each exhibit one or more characteristics that enhance the preparation, storage, and use of compound (I) as a pharmaceutical composition. Generally speaking, these characteristics are selected from enhanced thermal stability, improved solubility in aqueous solvents, improved bioavailability, ready isolation from water-wet solvents, and capacity to be formulated as a pharmaceutical composition using wet granulation techniques.
In relation to all other known forms of compound (I), the polymorph A form of anhydrous compound (I) exhibits greater thermal stability, which facilitates storage and formulation of pharmaceutical preparations.
In relation to the polymorph A form of anhydrous compound (I), the polymorph B form of anhydrous compound (I) exhibits greater solubility in aqeuous solvents, and is expected to demonstrate better bioavailability.
In relation to all other known forms of compound (I), the monohydrate of compound (I) is advantageously isolated from water wet solvents and can be formulated, for example tableted, using wet granulation techniques.
In relation to all other known forms of compound (I), the ethylene diamine (mono) salt of compound (I) exhibits greater solubility in aqeuous solvents and is expected to demonstrate superior bioavailability.
The present invention also relates to pharmaceutical compositions for the treatment of diseases induced by LTB4, or to which LTB4 contributes, that comprise, or are derived from, one of the aforementioned salt, hydrate, or polymorphic anhydrous crystalline forms of compound (I), in an amount effective to treat said disease, and a pharmaceutically effective carrier.
The present invention further relates to pharmaceutical compositions for the treatment of a disease state selected from inflammatory disorders such as rheumatoid arthritis, oseoarthritis, inflammatory bowel disease; disorders of the skin including psoriasis, eczema, erythma, pruritis, and acne; stroke, and any disease marked by reperfusion injury; graft rejection; autoimmune diseases; allergy and asthma; and any other condition where marked neutrophil infiltration occurs, wherein said pharmaceutical compositions comprise, or are derived from, one of the aforementioned salt, hydrate, or polymorphic anhydrous crystalline forms of compound (I), in an amount effective to treat said disease, and a pharmaceutically effective carrier.
With respect to pharmaceutical compositions and the preparation thereof, the invention also relates to pharmaceutical compositions that comprise compound (I), or any polymorph, salt, covalent derivative, solvate or hydrate thereof, where said compound is prepared in a process wherein a novel composition of the present invention is an intermediate or starting material therein.
The present invention also relates to a method for the treatment of diseases induced by LTB4, or to which LTB4 contributes. The present invention further relates to methods for the treatment of disease states selected from inflammatory disorders such as rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease; disorders of the skin including psoriasis, eczema, erythma, pruritis, and acne; stroke, and any disease marked by reperfusion injury; graft rejection; autoimmune diseases; allergy and asthma; and any other condition where marked neutrophil infiltration occurs. In the practice of said methods, there is administered a phamaceutical composition of the invention, itself comprising a novel salt, hydrate or polymorphic anhydrous crystalline form of compound (I) in an amount effective for treatment, and a pharmaceutical carrier.
With respect to treatment of diseases herein, the invention also relates to the administration of a pharmaceutical composition comprising compound (I), or a any polymorph, salt, covalent derivative, solvate or hydrate thereof, where said compound is prepared in a process wherein a novel composition of the present invention is an intermediate or starting material.
The invention further relates to a method for inhibiting the binding of LTB4 to a receptor therefor in a patient in need of said inhibition, said method comprising administering a pharmaceutical composition as aforementioned.
The invention further relates to a process for the preparation of a novel polymorphic forms of anhydrous crystalline compound (I), and to a novel salt and a hydrate of compound (I).
These and other features of the invention are more fully elaborated below.